3-tropanylidine derivatives of tricyclic compounds, their salts, and process of preparation

ABSTRACT

Tropane derivatives and acid addition and quaternary ammonium salts thereof, said tropane derivatives having the formula:   HYDROLYZING WITH WATER AND RESULTING MAGNESIUM COMPLEX AND   REACTING THE OBTAINED COMPOUND WITH A DEHYDRATING AGENT (A   ANHYDRID OR PHOSPHOROUS OXYCHLORIDE OR HYDROCHLORIC ACID).   IN WHICH X represents : -CH2-CH2-, -CH CH-,   and -CH2-S- . These products are useful in human therapeutics namely as antihistaminic, spasmolytic and antiparkinson medicines. Compounds of formula 1 are prepared by reacting the organomagnesium compound of 3 Beta -chlorotropane with a ketone of formula :   HYDROLYZING WITH WATER AND RESULTING MAGNESIUM COMPLEX AND REACTING THE OBTAINED COMPOUND WITH A DEHYDRATING AGENT (ACETIC ANHYDRID OR PHOSPHOROUS OXYCHLORIDE OR HYDROCHLORIC ACID).

United States Patent (191 1 3,725,415 [4s] Apr.3,19'73 Boissier et a1.

[75] Inventors: Jacques R. Boissier, Paris; Roger Ratouis, SaintCloud, both of France [73] Assignee: Societe anonyme dltetSociete Industrlelle pour La Fabrication des Antlbiotlques (S.I.F.A), Puteaux, 4 France 22' Filed: Oct. 21, 1969 [21] Appl. No.: 868,230

[30] Foreign Application Priority Data Oct; 22, 1968 France ..P.V. 170 767 Dec. 20, 1968 France ..68179397 [52] US. Cl ..260/292, 424/265 [51] Int. Cl. ..C07d 43/06 [58] Field of Search ..260/293.43, 293.44, 293 A, 260/292 [56] References Cited UNITED STATES PATENTS 1,915,334 6/1933 Salzbetg et al. ..260/243 3,014,911 12/1961 Engelhordt ...260l293.4 3,264,308 8/1966 van der Stelt ..260/292 FOREIGN PATENTS 0R APPLICATIONS 659,475 3/1963 Canada ..260/292 105,025 8/1966 Denmark ..260/293 A OTHER PUBLICATIONS 377-379, Villani et al.

Primary Examiner- Henry .liles Assistant Examiner-S. D. Winters Attorney-Davis, I-Ioxie, Faithfull & Hapgood 57] ABSTRACT Tropane derivatives and acid additionand quaternary ammonium salts thereof, said tropane derivatives hav-' ing the formula:

in which X represents CH,CI-l,-, CH=C1-1-,

CH3 CH3" and --C1-1,S

These products are useful in human therapeutics namely as antihistaminic, spasmolytic and antiparkinson medicines.

Compounds of formula 1 are prepared by reacting the organo-magnesium compound of 33- hydrolyzing with water and resulting magnesium complex and reacting the obtained compound with a 2 Claims, No Drawlngs 3-TROPANYLIDINE DERIVATIVES OF TRICYCLIC COMPOUNDS, THEIR SALTS, AND PROCESS OF PREPARATION 'as antihistaminic, spasmolytic and antiparkinson medicines. The new tropane derivatives, according to the invention, are represented by the formula:

(J E) X where X represents one of the following divalent radicals CH,CH,--, --CH=CH,

C53 /CH3 or CI-I,-S--.

According to the invention the process for the preparation of tropane derivatives of formula (1) comprises reacting the organo-magnesium compound of 3B-chlorotropance with a ketone of formula:

where X has the, meaning defined above, hydrolyzing with water the resulting magnesium complex, reacting the thus obtained compound of formula:

the compound of formula 3 is extracted with solvents from the reactive mixture.

b. dehydration of the compound of formula 3 is carried out in acetic acid with acetic anhydrid used in excess. The reaction is advantageously carried out with the hydrochloride of the compound" of formula (3) generated in situ with dry hydrogen chloride, the temperature of the reactive medium being maintained 0 between 50 C and the medium boiling point. When the reaction is over, the reactive mixture is poured into water in order to decompose the excess of acetic anhydrid, then made alkaline with sodium hydroxide and the resulting compound of formula 1 is extracted with a solvent. Said compound may eventually be then purified by extraction from the organic phase with an aqueous acid, alkalization of the aqueous phase, extraction with a solvent and concentration of the extracts.

also be effected by phosphorus oxychloride used in large excess and then also used as reactive medium, this reaction being advantageously performed at the boiling temperature of the reactive mixture. At the end of the reaction, the mixture is carefully poured into water in order to decompose the excess of phosphorus oxychloride, the obtained aqueous solution is made alkaline with sodium-hydroxide and the obtained compound of formula 1 is extracted with a solvent.-

The dehydration of the compound of formula 3 can also be effected by hydrochloric acid in this case a solution of the compound of formula 3 is boiled under reflux in a mixture of acetic acid and concentrated hydrochloric acid. At the end of the reaction, the solution is diluted with water and made alkaline with sodium hydroxide; the compound of formula 1 is then extracted with a solvent.

Compounds of formula 1 above described show a basic character and according to the invention, their acid addition salts are prepared by reacting the corresponding mineral or organic acids with the com-- pounds of formula 1, performing preferentially in a solvent. Preference is given to anhydrous solvents such as ethylether, ethanol and acetone. r

According to the invention, quaternary ammonium salts of compounds of formula 1 are prepared by reacting with the compounds of fonnula 1 the corresponding quaternizing agents, preferably in the presence of a solvent. Preference is given to anhydrous solvents such as ethylether, acetonitrile, acetone, dioxane, methanol, ethanol.

New tropane derivatives of formula 1 and their salts are very useful substances in human therapeutic, namely by their remarkable antihistaminic, parasympatholytic and anticholinergic properties. Results obtained in pharmacological study of these derivatives have been summarized in the table below, where are shown:

a. the protective efficient doses 50 (ED 50) of compounds against a dose of 0.8 mg/kg of histamine dihydrochloride administered by intravenous route in guinea pig. The injection of histamine was administered 30 minutes after the subcutaneous injection of the tested compound (LR. BOISSIER et al. chimie the'rapeutique 1967, No. 5 p. 323-328).

The dehydration of the compound of formula 3 can The ED. 50 of a compound is the dose protecting 50 percent of the tested animals against a single lethal dose of histamine.

b. the protective efficient doses 50 (E.D.50) of compounds against a close of 20 mg/kg of tremorine administered in mice by intraperitoneal route. The injection of tremorine has been effected 30 minutes after the intraperitoneal injection of the tested compound.

These ED. 50 represent the doses of compounds protecting 50 percent of tested animals against tremors (T) and parasympathomimetic reactions (PS) namely salivation, lacrimation, diarrhea, naturally induced by an injection of tremorine.

It appears that at a small dose the tested compounds are endowed with a very obvious peripheral and central anticholinergic activity.

c. the protective efficient doses 50 (ED 50) of compounds against sinistrotorsion induced in guinea pig by an intracarotid injection of 0.012 mg/kg of xotremorine. In the present experiment, the injection of oxotremorine has been effected 30 minutes after the subcutaneous administration of the tested compound (H. DIAMANT Acta otolaryngologica suppl. 111). Thus the important central anticholinergic activity of tested compounds was showed.

d. the lethal doses 50 (LD 50) evaluated in mice by intraperitoneal route. Death rate was noticed 48 hours after the injection and LD 50 doses were calculated according to BEHRENS-KARBERs method.

TABLE sons disease. The usual dose varies according to the used product, the treated patient, the concerned complaint and the selected administration route; it may be for instance from 5 mg to 100 mg per day, by oral route in human beings.

As medicines, new tropane derivatives of formula 1 may be employed either in the form of base or in the form of pharmaceutically acceptable acid addition salts or quaternary ammonium salts. Preference is given among the acid addition salts to those obtained with the following acids hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, maleic, fumaric, succinic, tartaric, citric, benzoic, alkane sulfonics, and among quaternary ammonium salts, to those obtained with alkylhalides, such as for instance methyl chloride, bromide or iodide, hydroxyalkyl halides such as, for instance, 2-hydroxyethyl chloride, bromide or iodide, alkyl sulfates such as, for instance, dimethyl sulfate, alkyl-alkane sulfonates or alkyl-arene sulfonates, such as methyl-methane sulfonate, methylbenzene sulfonate or methyl-toluene sulfonate.

The present invention concerns also pharmaceutical compositions which comprise as active principles one at least of the compounds of the formula 1 and/or their acid addition salts and/or quaternary ammonium salts. These compositions are prepared in order to be administered through digestive, parenteral or local route. They can be solid or liquid; the pharmaceutical compositions are those usually employed in human N dlHa Antagonism against- Tremorine ED Sinistro- Histamine in mgJkg. torsion LD Example ED 60 ED 60 in X N". Form in mgJkg- T PS in mgJkg. mgJkg.

CH=0H---..' s 0. (is-0.1 2 2 0.5-1 57 CH=CH. 10 0.05 10 1 10 25 CHz-CH2. 1 5 1 1 86 CHzCHz-- 3 z 1 i 0. 5 93 CHzCHz. 5 0. 2-0.5 10 0.5 510 31 C=(CHa)z 11 0.2-0.5 2 2 0.5-1 74 C=(CHa)z 12 2 5 0.5 5-10 28 CH2S 13 5 12 l-2 0. 2-0. 5 82 CH2S 14 5 1-2 1-2 1-2 95 this compound has been prior dissolved in diluted acetic acid.

Owing to their very interesting pharmacological activities and especially owing to their antihistaminic, parasympatholytic and anticholinergic properties, new tropane derivatives of formula 1, their acid addition salts and quaternary ammonium salts are very useful medicines, especially as antihistaminic, spasmolytic and antiparkinson drugs. They can thereby be employed in treatment of cutaneous allergic diseases (as for instance urticaria, contact dermatitis, eczemas, erythemas) allergic rhinitis, allergic asthma, gastritis,

spasmodic gastrointestinal disturbances and Parkinmedicine, as for instance tablets, coated or not, capsules, solutions, syrups, suppositories, parenteral preparations, ointments, creams, gels and aerosols; they are prepared according to usual means. The active principle or principles can be incorporated with excipients which are normally employed in those pharmaceutical compositions, such as for instance, talcum, arabic gum, lactose, starch, magnesium stearate, cocoa butter, aqueous or non aqueous vehicles, animal or vegetable fatty substances, paraffins, glycols, various wetting dispersing and emulsifying agents and preservatives.

The following non limiting examples illustrate the invention EXAMPLE 1 3-( 10,1 l-dihydro-SH-dibenzo ylidene) tropane.

The organo-magnesium compound of 3B- chlorotropane was prepared from 5.32 g (0.222 mg) of magnesium turnings and 35.4g (0.222 mole) of 3 B- chlorotropane in 200 ml of anhydrous tetrahydrofuran under dry nitrogen. A solution of 32 g (0.154 mole) of 10,11-dihydro-5H-dibenzo [a,d]-cyclohepten-S-ene in 50 ml of anhydrous tetrahydrofuran was then added. The mixture was boiled for 1 hour under reflux with stirring, left at room temperature overnight, poured into a mixture of 500 g of ice and 100 ml of water containing g of ammonium chloride and extracted with ether. The etheral solution was evaporated to give an [a,d -cyclohepten-5 oil which slowly crystallized and which was stirred with 50 ml of pentane. "Pentane was removed by filtration and the resulting solid collected to give 40 g (75 percent) of 3-(10,l 1-dihydro-5-hydroxy-5H-dibenzo [a,d]-cyclohepten-S-yl) tropane as cream-colored crystals. Melting point on a hot stage microscope after recrystallization from acetonitrile 183-l 85 C.

Analysis C H N 0 C 1'! Calculated 82.8 8.2 Found 82.6 8.3

40 g (0.12 mole) of 3-(10,1 l-dihydro-S-hydroxy-SH- dibe'nzo [a,d]-cyclohepten-S-yl) tropane were dissolved in 210 ml of acetic acid. Dry hydrogen chloride was bubbled through this solution for 30 minutes. Then, 60 g of acetic anhydrid were added and the solution was heated on water bath for 1 hour 30.

The resulting solution was poured into 1 liter of water and washed with ether. Aqueous phase was separated from ethereal phase by decantation, and basitied by addition of sodium hydroxide and extracted with chloroform. I

Chloroformic solution was concentrated to give an oil which was dissolved in 200 ml of ether, and added by ethanolic hydrochloric acid solution until acidity of the medium. The resulting precipitate was collected and suspended in 500 ml of water. The suspension was C H Calculated 87.6 8.0 Found 5 87.4 8.1

EXAMPLE 2 3-( 10,1 l-dihydro-SH-dibenzo ylidene) tropane hydrochloride.

[a,d]-cyclohepten-S- 6 One g of 3-(l0,ll-dihydro-SH-dibenzo [a,d]-

cyclohepten-S-ylidene) tropane was dissolved in 30 ml of anhydrous ether and stoichiometric amounts of an ethanolic hydrochloric acid solution were added. The resulting precipitate was collected to give 3-(10,11- dihydro-5H=dibenzo [a,d]-cyclohepten-5-ylidene) tropane hydrochloride as white crystals. Melting point on a hot stage microscope, after recrystallization from acetonitrile 300 C with decomposition.

Analysis C l-I cl N C H I Calculated 78.5 7.5 Found 78.7 7.5

EXAMPLE 3 3-( 10,1 l-dihydro-SH-dibenzo ylidene) tropane methanesulfonate.

Six g (0.19 mole) of 3-(10,1l-dihydro-SH-dibenzo [a,d]-cyclohepten-5-ylidene) tropane were dissolved in ml of anhydrous ether and stoichiometric amounts of methane sulfonic acid were added. The resulting precipitate was collected to give 5.3 g (64 percent) of 3-( 10,1 l-dihydro-Sl-I-dibenzo [a,d]-cyclohepten-S- ylidene) tropane methanesulfonate as water-soluble white crystals. Melting point on a hot stage microscope after recrystallization from a mixture acetone-ether 221-222C. Analysis C H N 0 S C H Calculated 70.0 7.1 Found 70.1 7.3

- pound.

EXAMPLE 4 3-(.l 0,1 l-dihydro-SH-dibenzo ylidene) tropane methiodide.

One g of 3-( 10,1 l-dihydro-SH-dibenzo [a,d]- cyclohepten-S-ylidene) tropane was dissolved in 30 ml of anhydrous ether and added with a solution of 2 ml of methyliodide in 30 ml of anhydrous ether. The mixture was left for 48 hours at 0 C. the resulting precipitate was collected to give 3-(10,1l-dihydrmSI-Ldibenzo [a,d]-cyclohepten-5-ylidene) tropane methiodide as white crystals. Melting point on a hot stage microscope after recrystallization from acetonitrile 332-333 C.

Analysis C l-[ 1 N C H Calculated 63.0 6.2 Found l: 63.1 6.1

[a,d] -cyclohepten-5- EXAMPLE [a,d]-cyclohepten-S- C H Calculated 68.0 7.1 Found 68.1 7.2

EXAMPLE 6 3-(5H-dibenzo [a,d]-cyclophepten-5-ylidene) tropane.

The organo-magnesium compound of 3B- chlorotropane was prepared from 5.5 g (0.23 at-g) of magnesium turnings and 36.5 g (0.23 mole) of 3B- chlorotropane in 200 ml of anhydrous tetrahydrofuran under dry nitrogen. The solution of 35.4 g (0.172 mole) of SH-dibenzo [a,d] cyclohepten-S-one in 200 ml of anhydrous tetrahydrofuran was then added, the mixture was refluxed for 1 hour with stirring and left at room temperature overnight. The reactive mixture was poured into a mixture of 500 g of ice and 100 ml of water containing 20 mg of ammonium chloride and extracted with chloroform. Concentration of the chloroformic solution give 46 g (60 percent) of 3-(5- hydroxy-SH-dibenzo [a,d]-cyclohepten-S-yl) tropane as cream-colored crystals. Melting point on a hot stage microscope after recrystallization from acetonitrile 186 188 C.

Analysis C l-MN O C H Calculated 83.3 7.6 Found 82.9 7.7

Twenty-three g (0.0695 mole) of 3-(5-hydroxy-5l-ldibenzo [a,d]-cyclohepten-S-yl) tropane were dissolved in 200 ml of phosphorus oxychloride and the mixture was boiled under reflux for 1 hour. The resulting solution was poured into 1 liter of water, made alkaline by addition of sodium hydroxide and extracted with chloroform. Concentration of chloroformic solution gave g (69 percent) of 3-(5H-dibenzo [a,d]- cyclohepten-S-ylidene) tropane as a crystalline solid. Melting point on a hot stage microscope after recrystallization from acetonitrile 183C.

Analysis C I-I N C H N Calculated 88.1 7.4 4.5 Found 88.1 7.4 4.4

EXAMPLE 7 3-(5H-dibenzo [a,d]-cyclohepten-5-ylidene) tropane.

Following the procedure described in example 1, but starting from 41 g (0.124 mole) of 3-(5-hydroxy-5I-ldibenzo [a,d] cyclohepten-S-yl) tropane, 3-(5H- dibenzo [a,d]-cyclohepten-S-yl) tropane was obtained as a crystalline solid identical with that described in example 6. Melting point on a hot stage microscope after recrystallization from acetonitrile 183C.

EXAMPLE 8 3-(5H-dibenzo [a,d]-cyclohepten-5-ylidene) tropane hydrochloride.

One g of 3-(5H-dibenzo [a,d,]-cyclohepten-5- ylidene) tropane was dissolved in 100 ml of anhydrous ether and stoichiometric amounts of an ethanolic hydrochloric acid solution were added. The resulting precipitate was collected to give 3-(5H-dibenzo [a,d]- cyclohepten-S-ylidene) tropane hydrochloride water-soluble white crystals. Melting point on a hot stage microscope after recrystallization from isopropanol 301-303 C.

Analysis C, H, Cl N C H N Calculated 79.0 6.9 4.0 Found '1: 78.7 7.0 4.0

EXAMPLE 9 microscope after recrystallization from acetonitrile 198-201C.

Analysis C l-1, 1 N

C H N Calculated 63.3 5.7 3.1 Found 63.5 5.8 3.1

EXAMPLE l0 3-(5H-dibenzo [a,d]-cyclohepten-5-ylidene) tropane dimethylsulfate.

1.5 g of 3-(5I-I-dibenzo [a,d]-cyclohepten-5-ylidene)- tro-pane was dissolved in ml of acetone and added with 5 ml of dimethyl sulfate. The mixture was left for 4 hours at 0 C and added with ml of anhydrous ether. The resulting precipitate was collected, recrystallized from isopropanol to give 1.1 g of 3*(5H- dibenzo [a,d]-cyclohepten-5-ylidene) tropane dimethylsulfate as water-soluble white crystals. Melting point on a hot stage microscope 240245 C.

Analysis C H N 0 5 C H N Calculated I: 68.3 6.7 3.2 Found I: 68.2 6.5 3.0

EXAMPLE l1 3-( l0,l-dimethy1-9,10-dihydroanthracen-9-ylidene) tropane.

The organo-magnesium compound of 3B- chlorotropane was prepared from 5.6 g (0.234 at-g) of magnesium turnings and 37.3 g (0.234 mole) of 3B- chlorot'roparie in 170 ml of anhydrous tetrahydrofuran under dry nitrogen. The solution of 40 g (0.18 mole) of 10,10-dimethyl-9-anthrone in 200 ml of anhydrous tetrahydrofuran was then added. The mixture was boiled under reflux while stirring for 1 hour, left at room temperature overnight, then poured into a mixture of 500 g of ice and 150 ml of water containing 20 g of ammonium chloride and extracted with chloroform. The chloroformic solution was concentrated to give a solid residue which was recrystallized from xylene, 1 1.5 g (19 percent) of 3-(9-hydroxy-10,10-dimethyl-9,l0- dihydroanthracen-9-yl) tropane, as cream-colored crystals, were obtained. Melting point on a hot stage microscope 265-267 C.

Analysis I C24H29N O a c H Calculated 82.9 8.4 Found 82.8 8.3

3-( 10,10-dimethyl-9,10-dihydroanthracen-9-ylidene) tropane as white crystals. Melting point on a hot stage microscope 200203 C.

under dry nitrogen. The mixture was then added with the solution of 42 g (0.185 mole) of dibenzo [b,e]-

of anhydrous.

Analysis C fi N 0 S j c H N Calculated 75.2 7.2 4.0 Found 75.0 7.1 4.0

Nine g (0.0256 mole) of 3-(6,11-dihydro-1 l-hydroxy dibenzo [b,e]-thiepin-11(6H)-yl) tropane were dissolved in the mixture of 100 ml of acetic acid and 40 ml of concentrated hydrochloric acidand' boiled under reflux for 1 hour.

The resulting solution was poured into 500 ml of water and extracted with ether. Aqueous phase was separated by decantation from ethe'real"phas' e,- basified by addition of sodium hydroxide, and extracted with ether. Ethereal solution was concentrated to'give 8 g of an oil which crystallized quickly and was recrystallized from acetonitrile. 3.5g (41 percent) of 3- dibenzo [b,e]-thiepin-1 l 6H)-ylidene tropane were obtained as a creamy solid. Melting point on a hot stage microscope 15 61 5 8C.

" Analysis C H' N c H N Calculated "5 87.5 8.3 4.3 Found 87.7 8.2 4.2

EXAMPLE l2 3-( 10,10+dimethyl-9,10-dihydroanthracen-9-ylidene) tropane dimethylsulfate.

Two'g of 3-(l0,10-dimethyl 9,l0-dihydroanthracen- 9-ylidene) tropane were dissolved in 100 ml of ether and added with 5 ml of dimethyl sulfate. After 5 minutes, the resulting precipitate was collected-to give I 3-(10,l0-dimethyl-9,lO-dihydroanthracen-9-ylidene) 'tropane'dim ethylsulfate as white crystals. Melting point after recrystallization from isopropanol 350 C.

Analysis: C,,H, N 0 S chlorotropane was prepared from 5.9 g (0.244 at-g) of magnesium turnings and 38.8 g (0.244 mole) of 3B- chlorotropane in 200 ml of anhydrous tetrahydrofuran Analysis C H 'N S H N" 'Cslculated% 79.3 7.0 4.2 Found% 79.5 a 6.9, 4.2

EXAMPLE 14,-

percent) of 3-dibenzo [b,e]-thiepin-l1 .(6H)#y.lidene tropane hydrochloride as white crystals. Melting point on ahot stage microscope: 272-274 C.

Analysis C l-MCI N S' c H cl' 5 Calculated 71.4 6.5 9.6 8.7 Found 71.0 6.5 9.2 8.5

EXAMPLE 15 S-dibenzo [b,e]-thiepin-1 l(6H)-.ylidene tropane ethobromide.

c H N Calculated 65.1 6.4 7.3 Found 64.9 6.3 7.3

EXAMPLE 16 3-dibenzo [b,e]-thiepin-11(6H)-ylidene tropane methyl methanesulfonate One g of 3-dibenzo [b,e -thiepin-ll(6H)-ylidene tropane was dissolved in 100 ml of ether and added with 5 ml of methylmethanesulfonate. The mixture was left for 48 hours at 0C, resulting crystals were collected and recrystallized from isopropanol to give 3- dibenzo [b,e]-thiepin-1 l(6H)-ylidene tropane methyl methanesulfonate as white crystals. Melting point on a hot stage microscope 243-245 C.

Analysis C l-[ N 0 S C H N Calculated 65.0 6.6 3.2 Found 65.0 6.7 3.1

EXAMPLE 17 Tablets were prepared which corresponded to the formula:

- B-(SH-dibenzo [a,d]-cyclohepten-S-ylidene) tropane hydrochloride Excipient s.q. to make (excipient lactose, starch, talcum, magnesium stearate) 10 mg 200 mg EXAMPLE 18 An ointment was prepared which corresponded to the formula S-(SH-dibenzo [a,dl-cyclohepten-S-ylidene) tropane hydrochloride Excipient s.q. to make EXAMPLE 19 Tablets were prepared which corresponded to the 5 formula:

- 3-( 10,1 l-dihydro-Sl-Ldibenzo [a,d]-

c clohepten- 5- idene) tropane dimethylsulfate 25 mg 6 Excipient s.q. to make 200 mg (excipient lactose, starch, talcum, magnesium stearate) EXAMPLE 2O Suppositories were prepared which corresponded to the formula 3(10,1l-dihydro-5l-l-dibenzo [a,d]-

cyclohepten- 5-ylidene) tropane dimethylsulfate 25 mg Excipient s.q. to make 3 g EXAMPLE 21 Parenteral preparations were prepared which corresponded to the formula:

- 3-(10,ll-dihydro-5H-dibenzo [a,d]-

cyclohepten- S-ylidene) tropane dimethylsulfate 20 mg Excipient sq. to make EXAMPLE 22 Drops were prepared which corresponded to the formula 3-( 10,1 l-dihydro-SH-dibenzo [a,d]-

cyclohepten- S-ylidene) tropane dimethylsulfate -Excipient s.q. to make EXAMPLE 23 Tablets were prepared which corresponded to the formula:

- 3-( 10,10-dimethyl-9,10-dihydroanthracen-9- ylidene) tropane dimethylsulfate 25 mg Excipient s.q. to make 200 mg (excipient lactose, starch, talcum, magnesium stesrate) EXAMPLE 24 Tablets were prepared which corresponded to the formula: 3-(10,11-dihydro-5H-dibenzo [a,d]- cyclohepten-S-ylidene) tropane methanesulfonate Excipient s.q. to make (excipient lactose, starch, talcum, magnesium stearate) 5 mg 200 mg EXAMPLE 25 Tablets were prepared which corresponded to the formula:

- 3-dibenzo [b,el-thiepin-l1(6l-l)-ylidene tropane 5 mg Excipient s.q. to make 200 mg (excipient lactose, starch, talcum, magnesium stearate) We claim: 1. A compound selected from the group consisting of tropane derivatives, their acid addition salts and their quaternary ammonium salts, said tropane derivatives having the formula: a

3,725,415 Y a- 1 L 14 whereXis C H\;C/CHa Q a 2. A compound selected from the group consisting of tropane derivatives, their acid addition salts and their quaternary ammonium' salts, said tropane derivatives WheYeX ls rhavingthe formula: I: a: 

2. A compound selected from the group consisting of tropane derivatives, their acid addition salts and their quaternary ammonium salts, said tropane derivatives having the formula: 